Andreas S. Lübbe

Physiological aspects in magnetic drug-targeting

The efficacy of magnetically-controlled drug targeting (MDT) depends on physiological parameters. To understand its mechanism of action on the tissue at the microcirculatory level, we identified the ferrofluids potential (its biological effects, its bioavailability and the in vivo desorption time of the anticancer drug epirubicin). Mechanical tumor embolization was possible, but successful tumor treatment was sometimes bypassed by a developing collateral circulation. Thus, MDT-treatment was used successfully in mice and in man.

Improvement of pneumonia and arthritis in Felty's syndrome by treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF).

SummaryA 63-year old man with Feltys syndrome and pneumonia of unknown origin was treated with GM-CSF. Granulocyte counts increased and arthritis-related symptoms improved under GM-CSF. Pneumonia was treated effectively with antibiotics only during or after GM-CSF application. This suggests, that antibiotic-resistent infections can be treated effectively in patients with Feltys syndrome when granulocyte counts are raised by GM-CSF.

Microcirculatory Responses to Complement Activation Are Blunted by Hypertension

Vasodilation of small arterioles in skeletal muscle during sepsis is an endothelium-dependent response. Renovascular hypertension significantly attenuates this response. Complement activation by zymosan infusion causes small arteriole dilation in skeletal muscle similar to that seen during sepsis. This study was conducted to show whether renovascular hypertension alters the skeletal muscle microcirculatory responses in normotensive rats to systemic activation of the alternative complement system. We found that hypertension abolished the constriction of large A1 arterioles (+3 +/- 2% change at 45 min) and dilation of small A4 arterioles (-2 +/- 2% change at 45 min) in skeletal muscle. Hypertension attenuated but did not abolish (A4: +70 +/- 13% change in hypertensive vs +111 +/- 18% in normotensive rats) the ability of small arterioles to dilate to nitroprusside, an endothelium-independent vasodilator. This suggest that hypertension modifies some type of receptor-level mechanism to reduce small arteriolar dilation during complement activation. We next used hydroquinone to topically block endothelium-derived relaxing factor (EDRF) in hypertensive animals whose complement systems were activated. Hydroquinone did not change the response of large A1 arterioles (+5 +/- 4% hydroquinone change vs +3 +/- 2% non-hydroquinone at 45 min) to complement activation. However, hydroquinone allowed construction of small A4 arterioles (-12 +/- 5% hydroquinone change vs -2 +/- 2%, non-hydroquinone at 45 min) during complement activation in hypertensive rats. We conclude that during hypertension the release of EDRF in small arterioles after complement activation is counterbalanced by a constrictor-producing mechanism.

Intraperitoneal Carboplatin in the Treatment of Bulky Disease Ovarian Cancer: Experience in Two Cases

Background : Intraperitoneal (i.p.) chemotherapy (CT) is an attractive treatment modality for cancers usually restricted to the peritoneal cavity. This seems to be particular true fo

Doxorubicin and local hyperthermia in the microcirculation of skeletal muscle

SummaryDoxorubicin HCl (Doxo) is an established intercalating antitumor drug. Specific side effects of Doxo primarily affect the cardiac muscle tissue to cause cardiac arrhythmias and chronic cardiomyopathies. The mechanism of action of these side effects is incompletely understood. Thus, the first objective of the present study was to test whether Doxo might have a direct effect on the microcirculation of muscular tissue. We studied large and small arterioles and large venules in the cremaster muscle of rats before and after sequential infusion of 1 (low-dose) and 10 mg/kg (high-dose) Doxo. Large arterioles showed some constriction after low Doxo doses and pronounced constriction after high Doxo doses, whereas small arterioles showed a variable response to low Doxo doses. At high Doxo doses, small arterioles dilated almost maximally (80% of the maximal response to nitroprusside). The heart rate and the diameter of large venules did not change at high Doxo doses, although the blood pressure decreased. This indicates that Doxo directly affects skeletal muscle arterioles. The second purpose of this study was to determine whether local hyperthermia would influence the microcirculation of muscular tissue such that the systemic concentration of Doxo could be reduced. In this second series of experiments, we tested whether local hyperthermia would have an effect on the skeletal muscle microvasculature and whether Doxo would change that response. Local hyperthermia alone did not alter the diameter of small arterioles or large venules, but we observed constriction of large arterioles at temperatures above 37°C and during continued (60-min) hyperthermia at 40°C. The low dose of Doxo did not alter these microvascular diameters at 40°C. However, local hyperthermia at 40°C changed the response of small arterioles to low doxo doses (no vasodilation was observed). Large arterioles continued to constrict in response to Doxo during hyperthermia. These data suggest that large arteriolar responses could be partly responsible for the toxic effect of Doxo on cardiac muscle and that local hyperthermia potentiates that response.